SIGNAL TRANSDUCTION
Cellular signal transduction is a fundamental mechanism whereby external stimuli regulate diverse cellular processes are relayed to the interior of cells. The process is generally initiated by the binding of extracellular factors (such as hormones and growth factors) to membrane receptors on the cell surface. The biochemical pathways through which signals are transmitted within cells comprise a circuitry of directly or functionally connected interactive proteins.
One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of tyrosine residues on proteins. The phosphorylation state of a protein may affect its conformation and/or enzymic activity as well as its cellular location. The phosphorylation state of a protein is modified through the reciprocal actions of protein tyrosine kinases (PTKs) and protein phosphotyrosine phosphatases (PTPs). Generally, the level of tyrosine phosphorylation increases after the cell has been stimulated by an extracellular factor. Research has largely focussed on the protein kinases (Sefton et al., 1980, Cell 20:807-16; Heldin and Westermark, 1984, Cell 37:9-20; Yarden and Ullrich, 1988, Ann. Rev. Biochem. 57:443-78; Ullrich and Schlessinger, 1990, Cell, 61:203-12).
Protein tyrosine kinases comprise a large family of transmembrane as well as cytoplasmic enzymes with multiple functional domains (Taylor et al., 1992, Ann. Rev. Cell Biol. 8:429-62). The binding of an extracellular factor or ligand allosterically transduces the signal to the inner face of the cell membrane where the cytoplasmic portion of the receptor protein tyrosine kinase (RPTKs) initiates a cascade of molecular interactions that disseminate the signal throughout the cell and into the nucleus.
Ligand-induced activation of the kinase domain and its signalling potential are mediated by receptor dimerization. Once activated, the receptor self-phosphorylates (autophosphorylation or transphosphorylation) on specific tyrosine residues of the cytoplasmic domain. (Schlessinger, 1988, Trends Biochem. Sci. 13:443-7, Schlessinger and Ullrich, 1992, Neuron, 9:383-91, and references therein).
Like the PTKs, the protein phosphotyrosine phosphatases (PTP) comprise a family of transmembrane and cytoplasmic enzymes. (Hunter, 1989, Cell, 58:1013-16; Fischer et al., 1991, Science, 253:401-6; Saito and Streuli, 1991, Cell growth and differentiation, 2:59-65; Pot and Dixon, 1992, Biochim. Biophys. Acta, 1136:35-43). As presently understood by those in the art, in general PTKs play a triggering role in signal transduction, while PTPs guarantee that the trigger is reset thereby serving to deactivate the pathway. However, the specific functions of PTPs have not yet been defined (Walton et al., 1993, Ann. Rev. Biochem., 66:101-20).
In addition to a homologous core catalytic domain, mammalian PTPs share diverse noncatalytic sequences. While some receptor protein tyrosine phosphatases (RPTPS) contain in their extracellular portions Ig-like and/or fibronectin type III repeats (e.g., LAR, Streuli et al., 1988, J. Exp. Med. 168:1523); others have small extracellular glycosylated segments (e.g., RPTP.alpha., Sap et al., 1990, Proc. Natl. Acad. Sci. USA, 87:6112; and RPTP.epsilon., Krueger et al., 1990, EMBO J, 9:3241). In all cases, the putative ligands have yet to be identified. Other phosphotyrosine phosphatases such as PTP1B, PTP.mu., PTP1C, TC-PTP, PTPH1, RPTP.kappa. and CD45 have been cloned and their cDNAs are described in Chernoff et al., 1990, Proc. Natl. Acad. Sci. USA, 87:2735-9; Gebbink et al., 1991, FEBS Lett. 290:123-30; Shen et al., 1991, Nature, 352:736-9; Jiang et al., 1993, Mol. Cell Biol., 13:2942-51 and; Charbonneau et al., 1988, Proc. Natl. Acad. Sci. USA, 85:7182-6 respectively.
Abnormal PTK/PTP signal transduction has been associated with a variety of diseases including psoriasis, cancer and diabetes.